17beta-hydroxy-3-oxoandrost-4-en-17alpha-ylpropionaldehyde lactol and delta1, delta6, delta1, 6, 19-nor and 7alpha-acetylthio congeners



United States Patent Ofifice 3,137,690 Patented June 16, 1 964 3,137,69017 B HYDROXY-S-OXOANDRQST-4-EN-17oc-YLPRO- PIONALDEHYDE LACTQL AND A ,A,A ,19-NOR AND 7oz-ACETYLTHIO CONGENERS William F. Johns, Morton Grove,Ill., assignor to G. D. Searle & Co., Chicago, 11]., a corporation ofDelaware N Drawing. Filed Sept. 26, 1963, Ser. No. 311,636 9 Claims.(Cl. 260-23955) This invention relates to l7fi-hydroxy-3-oxoandrost-4-en-l7a-ylpropionaldehyde lactol, to A ,A ,A ,19-nor and 7-alkanoylthiosteroids otherwise identical, and to processes whereby these various butcongeneric products can be manufactured. More particularly, thisinvention provides new, useful, and unobvious chemical compounds havingthe formula thio constituent is in alpha configuration on carbon atomnumber 7, thus S-alkanoyl Those skilled in the art will recognize thatthe subject lactols are epimeric with respect to the hydroxylated carbonatom in the lactol ring. Whereas such epimers are separable byfractional crystallization, their ready interconvertibility-catalyzed bytraces of either acid or base renders isolation infeasible as apractical matter, especially in view of the purposed use of thesesubstances (see below) in the animal body where the integrity of theseparation would be evanescent.

The compounds to which this invention relates are useful by reason oftheir valuable pharmacological properties. Thus, for example, they blockthe effects of desoxycorticosterone acetate on urinary sodium andpotassium.

.Manufacture of the 19-methyl compounds hereof starts with, inter alia,3 8,17,8-dihydroxy-17 a-(3-hydroxypropyl) androst-S-ene [J. Org. Chem.,26, 3077 (1961)], which is converted to the triacetate by heating withisopropenyl acetate in the presence of p-toluenesulfonic acid. Theprimary hydroxyl is selectively restored by adsorption on activatedalumina in petroleum ether and oxidized with cold chromium trioxide inpyridine to give the corresponding diacetoxy aldehyde. The diacetoxyaldehyde is converted to the diacetoxy dimethyl acetal by contactingwith methanol in the presence of p-toluenesulfonic acid, whereupon theacetoxy groups are cleaved by heating with ethereal lithium aluminumhydride. Op-

penauer oxidation affords the corresponding 4-en-3-one, which cyclizesto 17fi-hydroxy-3-oxoandrost-4-en-17a-ylpropionaldehyde lactol (amixture of epimers, as aforesaid) on standing in aqueous acetic acid.Alternatively, the 4-en-3-one is A dehydrogenated by heating withselenium dioxide and pyridine in tert-butyl alcohol and then cyclizedwith aqueous acetic acid to give17,8-hydroxy-3-oxoandrosta-1,4-diene-17a-ylpropionaldehyde lactol, orthe 4-en-3-one is A dehydrogenated by heating with chloranil intert-butyl alcohol and cyclized with aqueous acetic acid to17B-hydroXy-3-oxoandrosta-4,6- diene-17a-ylpropionaldehyde lactol. From17,8-hydroxy- 3-oxoandrosta-4,6-diene-17u-ylpropionaldehyde dimethylacetal, on heating with selenium dioxide and pyridine in tert-butylalcohol followed by aqueous acetic acid cyclization,17,8-hydroxy-3-oxoandrosta 1,4,6-triene-17a-ylpropionaldehyde lactol isobtained; and 17fl-hydroxy-3-oxoandrosta-4,6-diene-17a-y1propionaldehydelactol affords 7a-alkanoylthio-l7B-hydroxy 3oxoandrost-4-en-17m-ylpropionaldehyde lactol on contact with anappropriate thioalkanoic acid. Likewise, 17B-hydroxy-3-oxoandrosta-1,4,6-triene-17a-ylpropionaldehyde lactol affords 7a-alkanoylthio-178-hydroxy 3 oxoandrosta-1,4-diene-17a-ylpropionaldehyde lactol oncontact with thioalkanoic acid.

The 19-nor compounds of this invention eventuate from 3-( 17 B-hydroxy-3-methoxyestra-l ,3 ,5 10 -trien-17ayl)propionic acid lactone (US.2,875,199), which is reduced to17B-hydroxy-17a-(3-hydroxypropyl)-3-methoxyestra-1,3,5(10)-triene withlithium aluminum hydride in boiling ethereal tetrahydrofuran. Heatingthe diol thus obtained with isopropenyl acetate and p-toluenesulfonicacid gives the diester, which is heated with aqueous methanolicpotassium bicarbonate to regenerate the primary hydroxyl. The hydroxylis oxidized to an aldehyde group with cold chromium trioxide inpyridine, whereupon the dimethyl acetal is formed by contacting withmethanol and p-toluenesulfonic acid. Reduction with lithium in a mixtureof liquid ammonia and tert-butyl alcohol affords the corresponding2,5(10)-diene, from which 17B-hydroxy 3oxoestra-4-en-l7u-ylpropionaldehyde lactol is obtained on contact withaqueous acetic acid. The A derivative derives by cyclizing with methylorthoformate and p-toluenesulfonic acid in dioxane, oxidizing theresulting lactolide with manganese dioxide in benzene, and finallyhydrolyzing the lactolide with aqueous acetic acid. Interaction of17,8-hydroxy-3-oxoetra- 4,6-dien-17a-ylpropionaldehyde lactol andthioalkanoic acid affords the corresponding7a-alkanoylthio-17fi-hydroxy-3-oxoestra-4-en-17a-ylpropionaldehydelactol.

The following examples describe in detail compounds illustrative of thepresent invention and methods which have been devised for theirmanufacture. However, the invention is not to be construed as limitedthereby, either in spirit or in scope, since it will be apparent tothose skilled in the art of organic synthesis that many modifications,both of materials and of methods, may be practiced without departingfrom the purpose and intent of this disclosure. Throughout the exampleshereinafter set forth, temperatures are .given in degrees centigfade andrelative amounts of materials in parts by weight, except as otherwisenoted. Specific rotations were determined in chloroform solution (1%) atroom temperatures and refer to the D line of sodium.

Example 1 A. 3,8,17B diacetoxy 17zz-(3 acetoxypr0pyl)androst- 5 -ene.-Amixture of 780 parts of 3B,17'B dihydroxy-17a-(3-hydroxypropyl)androst-S-ene, 19 parts of p-toluenesulfonic acid, andapproximately 7000 parts of isopropenyl acetate is distilled to /2volume during 3 hours, then filtered. The filtrate is partitionedbetween benzene and water. The benzene phase is consecutively washedcomprising ethyl acetate in solvent, there is obtained as theandrost-S-en-l7 x-ylpropionaldehyde dimethyl acetal.

and stripped of solvent by distillation.

with aqueous potassium bicarbonate and water, then dried over anhydrousmagnesium sulfate and stripped of solvent by vacuum distillation. Theresidue is crystallized from methanol to give3,6,17p-diacetoxy-17a-(3-acetoxypropyl)androst-5-ene melting atapproximately 115-116, and further characterized by a specific rotationof 76.

B. 3 3,] 718 dzacetovcy 17oz (3-hydroxypr0pyl) androst- 5-ene.Ananhydrous solution of 80 parts of35,17l3-diacetoxy-l7a-(3-acetoxypropyl)androst-S-ene in 880 parts partsof ether and, finally, 5400 parts oration of solvent, there is obtainedas the residue, 35,175- diacetoxy-l7a-(3-hydroxypropyl)androst-S-enewhich, re-

7 crystallized from petroleum ether, melts at approximately 104-105 Theproduct is further characterized by a specific rotation of 85 C. 3,8,1718 diacetoxyandrost 5 en 17a ylpropionaldehyde.To a slurry of 100 partsof chromium trioxide in 1000 parts of pyridine is added a solution of102 parts of 3 ,6, 17 B-diacetoxy- 17a- (3-hydroxypropyl) androst-S-enein 1000 parts of pyridine, temperatures of the order of 5 beingmaintained throughout the addition and for 65 hours thereafter. Theresultant mixture is partitioned between water and ether. The etherphase is dried over anhydrous magnesium sulfate and stripped of solventby vacuum distillation. The residue is taken up in benzene andchromatographed on silica gel, using benzene and ethyl acetate asdeveloping solvents. From an eluate comprising 5% ethyl acetate inbenzene, on distillation of solvent, there is obtained as the residue,3,8,17,8-diacetoxyandrost-S-en-l7a-ylpropionaldeyde.

D. 3 3,175 diacetoxyandrost 5 en 17a ylpropionaldehyde dimethylacetal.--A solution of 90 parts of 319,l7fi-diacetoxyandrost-5-en-l7ot-ylpropionaldehyde and 2 parts ofp-toluenesulfonic acid in 790 parts of methanol is allowed to stand atroom temperatures for 25 minutes, then filtered. The filtrate is madealkaline with aqueous potassium bicarbonate and thereupon extracted withbenzene. The benzene extract is washed with Water, dried over anhydrousmagnesium sulfate,

and stripped of solvent by vacuum distillation. The residue is taken upin ben- 'zene and chromatographed on silica gel, using benzene and ethylacetate as developing solvents. From an eluate benzene, on distillationof residue, 35,17B-diacet0xy- E. 3,8,1713 dilzydroxyandrost 5 en 17aylpropz'onaldehyde dimethyl acetal.To a solution of 75 parts of lithiumaluminum hydride in 7000 parts of ether is added, with agitation duringapproximately 10 minutes, a solution of 305 parts of35,l7fi-diacetoxyandrost-5-en-17aylpropionaldehyde dimethyl acetal in7000 parts of ether. The resultant mixture is heated at the boilingpoint under reflux for 30 minutes and then cooled, whereupon sulficientwater is slowly introduced to destroy excess hydride.

Approximately 100 parts of aqueous 10% potassium hy-t droxide is thenmixed in, whereupon the ethereal phase is separated, dried overanhydrous magnesium sulfate, The residue, on recrystallization fromether, affords 3/9,l7 8-dihydroxyandrost-S-en-l7a-ylpropionaldehydedimethyl acetal melting at approximately 146-147 F. I7fl-hydroxy 3oxoandrost 4 en I 7oc-ylpr0pi0naldehyde dimethyl acetal.To a solution of12 parts of 3 5,17B dihydroxyandrost-S-en-17a-ylpropionaldehyde di-.methyl acetal in a mixture of 1350 parts of toluene and parts ofredistilled cyclohexanone at the boiling point under reflux in anitrogen atmosphere is added, with agitation, 27 parts of toluenecontaining 6 parts of aluminum isopropoxide. Heating at the boilingpoint under reflux with agitation in a nitrogen atmosphere is continuedfor an additional 15 minutes, whereupon approximately 500 parts ofsaturated Rochelle salt solution is introduced and the resultant mixturevigorously steamed distilled for minutes. The distilland is partitionedbetween water and benzene. The benzene phase is separated, consecutivelywashed with aqueous potassium bicarbonate and water, dried overanhydrous magnesium sulfate, and stripped of solvent by vacuumdistillation. The residue, upon recrys tallization from ether, affordsl7fl-hydroxy-3-oxoandrost- 4-en-17a-ylpropionaldehyde dimethyl acetalmelting at 143-145 G. hydroxy-3-oxoandrost-4-en-17ol-ylpropionaldehydelactoL-A solution of 35 parts of 17B-hydroxy-3-oxoandrost-4-en-l7u-ylpropionaldehyde dimethyl acetal in 2000 parts ofaqueous 70% acetic acid is allowed to stand at room temperatures for 3hours and then diluted with suflicient water to precipitate acrystalline product. The product, isolated by filtration and furtherpurified by recrystallization from a mixture of ether and petroleumether, is l7B-hyclroxy 3 oxoandros-t-S-en-l7tx-ylpropionaldehyde lactolmelting at 139-141. The product has Had Example 2 A. 17fl-hydr0xy-3-oxaandrosta-I,4-dien-17a-ylpropionaldehyde dimethylacetal.-A solution of 30 parts of 175 hydroxy 3oxoandrost-4-en-17u-ylpropionaldehyde dimethyl acetal and 16 parts ofselenium dioxide in approximately 3100 parts of tert-but'yl alcoholcontaining 10 parts of pyridine is heated at the boiling point underreflux for 24 hours. The resultant mixture is filtered throughinfusorial earth, and the filtrate is stripped of solvent by vacuumdistillation. The residue is taken up in chloroform; and the chloroformsolution is consecutively washed with water and aqueous potassiumbicarbonate, then stripped of solvent by vacuum distillation. Theresidue thus obtained is dissolved in benzene and chromatographed onsilica gel, using benzene and ethyl acetate as developing solvents. Froman eluate comprising 10% ethyl acetate in benzene, on evaporation ofsolvent, there is obtained17,8-hydroxy-3oxoandrosta-l,4-dien-17u-ylpropionaldehyde dirnethylacetal as the residue.

B. I7B-hydroxy3-0x0czndr0sfa-1,4-dien-l 741') lpropionaldehyde lactol.Asolution of 1 part of 17 8-hydroxy-3- oxoandrosta1,4-dien-17a-ylpropionaldehyde dimethyl acetal in 4 parts of aqueous 70%acetic acid is allowed to stand at room temperatures for 3 hours, thenprecipitated with excess water. The precipitate is collected on a filterand dried in air. The product thus isolated is 173- hydroxy3-oxoandrosta-l,4dien-17a-ylpropionaldehyde OH I O lactol, having theformula Example 3 A.17fl-hyaroxy-3-ox0androsta-4,6-dien-17a-ylpropionaldehyde dimethylacetal.A mixture of 10 parts of 1713- hydroxy 3oxoandrost-4-en-17a-ylpropionaldehyde dimethyl acetal and 37 parts ofchloranil in 2800 parts of tert-butyl alcohol is heated at the boilingpoint under re flux with agitation for 3 hours, then filtered. Thefiltrate is stripped of solvent by vacuum distillation. The residue is17 B-hydroxy 3 oxoandrosta-4,6-dien17a-ylpropionaldehyde dimethylacetal.

B. 1 7fi-hydroxy-3-ox0androsta-4,6-dien-1 7a-ylpr0pi0naldehyde lactl.-Asolution of 5 parts of 17/3-hydroxy-3- oxoandrosta 4,6dien-17a-ylpropionaldehyde dimethyl acetal in 300 parts of aqueous 70%acetic acid is allowed to stand at room temperatures for 3 hours.Sufficient water is thereupon introduced to effect precipitation. Thesolid product thrown down is filtered off and dried in air. The materialthus isolated is 17B-hydroxy-3-oxoandrosta-4,6-dien-17a-ylpropionaldehyde lactol, havingthe formula A. 175 hydroxy-S -oxoandr0sta-1 ,4,6-trien-1 7a-ylpr0-pionaldehyde dimethyl acetal.A mixture of 10 parts of 175hydroxy-3-oxoandrosta-4,6-dien-17a-ylpropionaldehyde dimethyl acetal, 5parts of selenium dioxide, 2 parts of pyridine, and 800 parts oftert-butyl alcohol is heated at the boiling point under reflux in anitrogen atmosphere for 36 hours, then diluted with 900 parts of ethylacetate and filtered through infusorial earth. The filtrate is strippedof solvent by vacuum distillation. The residue is taken up in benzeneand chromatographed on silica gel, using benzene and ethyl acetate asdeveloping solvents. From an eluate comprising 10% ethyl acetate inbenzene, on evaporation of solvent, there is obtained as the residue, 1718 hydroxy 3 oxoandrosta-1,4,6-trien-l7a-ylpropionaldehyde dimethylacetal.

B. 17,3 hydr0xy-3-0x0androsta-1,4,6-trien-17a-ylpropionaldehydelactol.Substitution of 1 part of 17B-hydroxy 3oxoandrosta-1,4,6-trien-l7a-ylpropionaldehyde dimethyl acetal for the17B-hydroxy-3-oxoandrosta-1,4- dien-l7a-ylpropionaldehyde dimethylacetal called for in Example 2B affords, by the procedure theredetailed, 1718- hydroxy 3 oxoandrosta-1,4,6-trien-l7a-ylpropionaldehydelactol, having the formula Example 5 is thereupon removed by vacuumdistillation at room temperatures. The residue crystallizes ontrituration with "methanol. The crystalline product is separated byfiltration and dried in air. The material thus isolated is 7aacetylthio17p hydroxy-3-oxoandrost-4-en-17a-ylpropionaldehyde lactol, having theformula "sooorn Example 6 H3O fl 'sooorn Example 7 A. hydroxy 17a (3hydroxypropyl) 3 methoxyestra-1,3,5 (10)-triene.To a solution of 10parts of lithium aluminum hydride in 700 parts of ether is added, withagitation during 10 minutes, a solution of 17 parts of 3- 17fi-hydroxy-3-mcthoxyestra-l ,3 ,5 10) -triene- 17a-yl)propionic acid lactone in 270parts of tetrahydrofuran and 700 parts of ether. The resultant mixtureis heated at the boiling point with continued agitation for 4 hours,whereupon excess hydride is decomposed with ethyl acetate. To themixture thus obtained is consecutively added 30 parts of water and 10parts of aqueous 10% potassium hydroxide. Upon filtration and vacuumdistillation of solvent from the filtrate, one obtains 1778- hydroxy1'70; (3 hydroxypropyl) 3 methoxyestra- 1,3,5(l0)-triene.

B. 175 acetoxy 17a (3 acetoxypropyl) 3 methoxyestra 1,3,5(10)-triene.-.A solution of 15 parts of 17 ,8hydroxy-17a-(3-hydroxypropyl)-3-methoxyestra- 1,3,5(l0)-triene and 6parts of p-toluenesulfonic acid in approximately 2700 parts ofisopropenyl acetate is distilled to /2 volume during 3 hours, thenfiltered and partitioned between ether and aqueous potassiumbicarbonate. The ethereal phase is separated, washed with water, driedover anhydrous magnesium sulfate, and stripped of solvent by vacuumdistillation. The residue is taken up in benzene and chromatographed onsilica gel, using benzene and ethyl acetate as developing solvents. Froman eluate comprising 2% ethyl acetate in benzene, on evaporation ofsolvent and recrystallization of the residue from aqueous methanol,there is obtained l7B-acetoxy-17a-(B- E acetoxypropyl) 3 methoxyestra1,3,5 10) triene melting at approximately 88-89".

C. 17,8 acetoxy 17a (3 hydroxypropyl) 3 methoxyestra 1,3,5(10) triene.-Amixture of a solution of 23 parts of 17fl-acetoxy-l7a-(3-acetoxypropyl)-3-methoxyestra-l,3,5(l0)-triene in 1600 parts of methanol with asolution of 50 parts of potassium bicarbonate in 200 parts of water isheated at the boiling point under reflux for 1 hour, then precipitatedwith water. The precipitate is filtered ofi and recrystallized from amixture of acetone and petroleum ether to give 17,8-acetoxy-17a-(3-hydroxypropyl) -3-methoxyestra-l ,3,5 (10) -triene melting at163-165".

D. 17,6 acetoxy 3 methoxyestra I,3,5(10) trien- 17a-ylpropi0naldehyde.Toa slurry of 70 parts of chromium trioxide in 700 parts of pyridine isadded, with agitation at temperatures not to exceed 5, a solution of 45parts of 17,8acetoxy-17a-(3-hydroxypropyl)-3-methoxyestra-l,3,5()-trienein 300 parts of pyridine. The resultant mixture is allowed to warm toroom temperatures over 2 hours with agitation, then partitioned betweenWater and ether. The ethereal phase is separated, dried .over anhydrousmagnesium sulfate, and stripped of solvent by vacuum distillation. Theresidue is taken up in benzene and chromatographed on silica gel, usingbenzene and ethyl acetate as developing solvents. From an eluatecomprising 2% ethyl acetate in benzene, on evaporation of solvent andrecrystallization of the residue from a mixture of ether and petroleumether, there is obtained .175 acetoxy 3 methoxyestra 1,3,5 (10) trien17ozylpropionaldehyde melting at approximately 142-143 E. 175 acetoxy 3methoxyestra 1,3,5(10) trien- J7u-ylpr0pi0naldehyde dimethyl acetal.-Toa slurry of 25 parts of17fi-acetoxy-3-methoxyestra-1,3,5(10)-trienel7a-ylpropionaldehyde in 400parts of methanol is added 3 parts of p-toluenesulfonic acid. Solutionoccurs. Excess aqueous potassium bicarbonate is added, and the solidprecipitate thrown down is collected on a filter. The product thusisolated is l7 3-acetoxy-3-methoxyestra- 1,3,510)-trien-l7a-ylpropionaldehyde dimethyl acetal.

F. 17,8 hydroxy 3 methoxyestra 2,5 (10) dienl7ot-ylpropionaldehydedimethyl acetal.-To a mixture of 240 parts of liquid ammonia and 120parts of tert-butyl alcohol is added a solution of 10 parts of1'7,B-acetoXy-3- methoxyestra-l ,3,5 l0) -trien-l7a-ylpropionaldehydedimethyl acetal in 135 parts of tetrahydrofuran. To the resultantmixture is added, with vigorous agitation, 4 one-part portions oflithium wire during 1 hour. After 3 hours, sufficient methanol(approximately 16 parts) is introduced to decolorize the mixture,whereupon the ammonia is distilled off and the distilland partitionedbetween water and benzene. The benzene phase is dried over anhydrousmagnesium sulfate and chromatographed on alumina to give175-hydroxy-3-methoxyestra-2,5(10)- dien-l7oc-ylpropionaldehyde dimethylacetal.

G. 17,3 hydroxy 3 oxoestra 4 en 17cc ylpropionaldehyde lactol-A solutionof 1 part of 17,6-hydroxy 3-methoxyestra-2,5(10)-dien-l7a-ylpropiona1dehyde dimethyl acetal in 4parts of aqueous 70% acetic acid is allowed to stand at roomtemperatures for 3 hours, then precipitated with water. The solidproduct thrown down is17,8-hydroxy-3-oxoestra-4-en-17a-ylpropionaldehyde lactol, which isisolated by filtration and dried in air. The product has the formulaNWOH 8 Example 8 A. 17,8hydr0xy-3-meth0xyestra-3,5-dien-17ol-ylpropionalrlehyde methyllactolide.-To a solution of 10 parts of 17,6 hydroxy3-oxoestra-4-en-l7a-ylpropionaldehyde lactol in 200 parts of dioxane and45 parts of methyl orthoformate is added 1 part of p-toluene-sulfonicacid. The resultant mixture is allowed to stand at room temperatures for30 minutes, then diluted with parts of pyridine followed by 1000 partsof water. The crystalline product which precipitates is17fi-hydroXy-3-methoxyestra-3,5-dien-l7a-ylpropionaldehyde methyllactolide. .The product is isolated by filtration and dried in air.

B. 1 7 ,d-hydroxy-3-oxoestra-4fi -dien-1 7 OP) lpropionaldehyde methyllactolide.-A mixture of 1 part of 17B-hydroxy 3methoxyestra-3,S-dien-17a-ylpropionaldehyde methyl lactolide, 5 parts ofmanganese dioxide, and approximately 90 parts of benzene is maintainedwith agitation at room temperatures for 1 hour, then filtered. Thefiltrate is stripped of solvent by vacuum distillation. The residue istaken up in benzene and chromatographed on silica gel, using benzene andethyl acetate as developing solvents. From an eluate comprising 10%ethyl acetate in benzene, on evaporation of solvent, there is obtainedl7,13-hydroxy-3-oxoestra-4,6-dien-l7ot-ylpropion aldehyde methyllactolide.

C. 17 8-hydroxy-S-0x0estra-4,6-dien-17a-ylpropionaldehyde lact0l.Amixture of 1 part ofl7fi-hydroxy-3-oxoestra-4,6-dien-l7a-ylpropionaldehyde methyl lactolideand 65 parts of aqueous 70% acetic acid is maintained with agitation atroom temperatures for 3 hours. Sufiicient Water is thereupon introducedto effect precipitation. The precipitate is collected on a filter anddried in air. The product thus isolated is1718-hydroxy-3-oxoestra-4,6-dienl7a-ylpropionaldehyde lactol, having theformula Example 9 70c acetylthio 1 7 fi-hydroxy-3-ox0estra-4-en-J 7a-ylpropionaldehyde lact0l.A mixture of 1 part of l7 3-hydroxy 3oxoestra-4,6-dien17u-ylpropionaldehyde lactol and approximately 2 partsof thioacetic acid is maintained with agitation at room temperatures for24 hours.

'Excess acid is thereupon removed by distillation in vacuo OH l 0 Had 9What is claimed is: l. A compound of the formula wherein Z is selectedfrom the group consisting of ethylene and vinylene radicals, Z isselected from the group consisting of ethylene, vinylene, and acetylthioethylene radicals so positioned in the steroid nucleus that theacetylthio constituent is in alpha configuration on carbon atom number7, and R is a methyl radical except when Z is an ethylene radical, fromthe group consisting of hydrogen and the methyl radical.

in which case R is selected 2. 175hydroxy-3-oxoandrost-4-en-17u-ylpropi0nalde hyde lactol.

3. 17 ,6 hydroXy-3-oxoandr0sta-l,4-dien-l7a-ylpropionaldehyde lactol.

4. 176 hydroxy 3 oxoandrostal,6-dien-17a-ylpropionaldehyde lactol.

5. 175 hydroxy 3 oxandrosta-l,4,6-trien-l7a-ylpropionaldehyde lactol.

6. 7a acetylthio 175 hydroxy-3-oxoandrost-4-enl7a-ylpropionaldehydelactol.

7. acetylthio-17,3-hydroxy-3-oxoandrosta-1,4-dien- 17a-ylpropionaldehydelactol.

8. 35,178 diacetoxyandrost 5 en 17a ylpropionaldehyde.

9. 17B acetoxy 3 methoxyestra 1,3,5 (10) trienl7a-ylpropi0naldehyde.

Patchett et a1 Mar. 26, 1963 Patchett Sept. 10, 1963 UNITED STATESPATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,137,690 June 16,l964 William F. Johns It is hereby certified that error appears in theabove numbered patent requiring correction and that the said LettersPatent should read as corrected below.

Column 1, lines 39 to 44, the formula should appear as shown belowinstead of as in the patent:

Salkanoyl column 2, line 46, for "0xoetra" read -oxoestracolumn 8, line6, for "toluene-sulfonic" read toluenesulfonic column 9 line 16, for"acetyl thioethylene"' read acetylthioethylene column 10, line 7, for"oxandrosta" read oxoandrosta Signed and sealed this 22nd day ofDecember 1964.

(SEAL) Attest:

ERNEST W. SWIDER EDWARD J BRENNER Attesting Officer Commissioner ofPatents

1. A COMPOUND OF THE FORMULA